Brain metabolism is a fundamental aspect of biology and human disease. The brain critically depends on glucose, consuming large quantities as the biochemical fuel for cognition, memory, and behavior. Fundamental aspects of brain metabolism have been extensively studied, but recent evidence regarding the key role of glucose and glycogen metabolism in neurological diseases has recently opened up new avenues of research. The neurological disease where aberrant glucose metabolism has been investigated in-depth is Lafora disease (LD). LD is an autosomal recessive, fatal, glycogen storage disease (GSD) that equally affects both sexes. Symptoms emerge in adolescence with drug-resistant epilepsy, ataxia, neurodegeneration, and a rapid decline into a vegetative state before death. Results from several labs using multiple models have demonstrated that aberrant intracellular glycogen-like aggregates, known as polyglucosan bodies (PGBs), are the cause of LD. Strikingly, we and others have identified PGBs in multiple neurological diseases and we hypothesize that PGBs are a driving force in disease progression for brain-impacted GSDs, and that PGBs also play a critical role in Alzheimer?s disease (AD). We have made foundational discoveries regarding glucose hypometabolism in LD, defined how PGBs impact cellular processes, developed cutting-edge tools to determine the underlying cellular mechanisms, and established therapeutic platforms to inhibit and/or eliminate PGBs. Defining the mechanisms of glycogen metabolism in LD provides insights into how PGBs form and impact brain homeostasis. Thus, LD offers a unique window into both normal brain glucose metabolism and broader disease implications when this metabolism is perturbed. This R35 will combine our NINDS-funded, LD-centric R01 and P01, and extend our expertise to brain- impacted GSDs and determining the role of PGBs in AD. Moving forward, we will further define LD-driven perturbations in signaling at the molecular level, elucidate changes in cellular physiology, and establish novel therapeutic modalities at the organismal level. Excitingly, the work on LD serves as a model for how to interrogate brain metabolic perturbations in other neurological diseases involving PGBs. We will apply these powerful LD-developed tools and insights to define how PGBs impact multiple neurological diseases, determine the glycogen-centric molecular mechanisms impacting disease progression, and define how PGB removal affects brain metabolism as a pre-clinical therapeutic. Importantly, we have key pieces of preliminary data for LD, brain-impacted GSDs, and AD from both mouse models and patient tissue. The increased stability, freedom, and flexibility provided by the R35 would allow us to make seminal discoveries in brain metabolism and define the role of PGBs in multiple diseases while carrying out key steps in the development of therapies and biomarker development. !